RESEARCH

DIRECTIONS

The FOXP2 story

A tale of genes, language
and human origins
A single family with speech
abnormalities may hold one of
the keys to the origin of
human culture.

or most of us, learning to speak in

our mother tongue is so natural
and instinctive that we need no
formal instruction. And natural
seems to equate, at least in part, to in our
genes, as studies of identical and nonidentical twins to tease out the genetic and
environmental components of this trait
have shown. These are the genes that set
us apart from our closest primate relatives
and equip us with the unique
combination of physical, articulatory and
neurological features necessary for spoken
language again.
Dr Simon Fisher, a Royal Society
Research Fellow at the Wellcome Trust
Centre for Human Genetics in Oxford,
was studying for his PhD when he
came across Steven Pinkers book,
The Language Instinct, which speculates
on the genetic basis of speech development. He was intrigued by Pinkers
ideas. Now, almost ten years later, he is
setting up a research group to look at the
molecular basis of speech and language
development. His research revolves
around a key discovery made in the laboratory of Professor Tony Monaco, director
of the centre in Oxford that of the
first gene shown to be necessary for the
acquisition of spoken language.

Gene hunting
The trail to the new gene, known as
FOXP2, began in 1996 when Professor
Monaco was approached by clinicians
working at the Institute of Child Health
in London who had been treating a

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Above:A molecular
model of the
FOXP2 protein.
The green segment
is the region
mutated in a
family with a
severe speech and
language disorder.

Right: Chat line:

Changes in FOXP2
may have paved the
way for the
development of
language.

unique family
with a severe
speech and language disorder (the
KE family). Unlike all the
other families with speech
and language disorders that
Professor Monacos group was studying
at the time in which the disorder is
inherited in a complicated way due to
the interplay of many different genetic
factors the KE familys disorder was
inherited in a simple fashion and as the
result of a defect in a single gene.
About half the family, which spans
three generations, suffer from the disorder. They have trouble controlling fine
movements in the lower half of their face,
and this gives them problems when making the complicated sounds necessary for
speech, explains Dr Fisher. In addition
to this problem, they have a variety of
problems in both spoken and written language and grammar. For example, says
Dr Fisher, if you ask them to write down
as many words as they can think of beginning with a particular letter, they dont do
very well and that defect is clearly not
related to articulation.

Dr Fisher and Cecilia Lai, a colleague

in Professor Monacos laboratory,
embarked on the hunt for the defective
gene in the KE family and successfully
tracked it down with the help of molecular signposts or markers to a region on
chromosome 7 containing between 50
and 100 genes. We went through every
candidate gene in the region relating to
brain function, says Dr Fisher, looking
through 20 and keeping another 50 or so
on the backburner. Then the trawl was
cut short by a stroke of luck.
We were on the look-out for individuals with a speech disorder who had a
chromosomal abnormality, explains
Dr Fisher, because there is a history of
these being involved in the mapping of
single gene disorders such as Duchenne
muscular dystrophy. Quite independently, however, a patient was referred to
Professor Monacos group by a local clinician who noted the strong resemblance
between her patients speech problems
and those of the unrelated KE family. The
problems in the patient, known as CS,
were associated with a chromosomal
abnormality in which large segments
from the ends of two different chromosomes had swapped around. One of the
chromosomes involved was chromosome
7 and the breakpoint appeared to be close
to the region implicated in the KE family.
Realizing that the gene search in the
KE family and in CS had fortuitously
converged, the group quickly pressed on
with microscopic techniques to narrow
down the breakpoint. They alighted on a
partially characterized gene, subsequently
named FOXP2. It was exciting,
remarks Dr Fisher, but we initially
sequenced the known half of the gene
and the mutation wasnt in there.
However, once the rest of the gene was

Wellcome News Q1 2003

RESEARCH
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pulled out and the sequence completed,

the group quickly identified a single basepair mutation in the sequence of the gene
that was specific to affected members of
the KE family. The gene responsible for
the speech defect in both the KE family
and in CS had been caught.

Inside FOXP2
Dr Fisher admits that he was initially
sceptical when the group fished out the
gene and mutation. I thought it was
going to be difficult to convince people,
he says. But there turned out to be a
precedence for mutations in the family of
genes to which FOXP2 belongs the
forkhead family of transcription factors.
Transcription factors switch on and off
other genes in the cell and are key players
in directing cell specialization and pattern formation during development.
In fact, the forkhead family acquired its
rather unusual name thanks to the
bizarre spiked-head structures found in
fruit fly embryos which had mutations in
the original forkhead gene. In humans
too, mutations in several genes in the
forkhead family have been identified as
the cause of certain developmental disorders such as congenital glaucoma and
immune deficiency.
The mutation found in FOXP2 in the
KE family lies in a critical region of the
encoded protein, leaving the cell reliant
on just one copy of the normal gene.

Though studies in mice indicate that

FOXP2 may also be important in the
development of the gut, heart and lungs,
it seems that these organs can get by
with a half-dose of FOXP2 in the KE
family, these organs function normally
whereas the brain appears to be particularly sensitive to lower levels of FOXP2.
The discovery of FOXP2 is a breakthrough for researchers looking for a handle on the molecular components of
speech and language development.
As Dr Fisher points out, There arent
really any convincing molecular biology
theories as starting points for speech and
language disorders. His group is embarking on a variety of studies to try and
elucidate the role of FOXP2 during development. We need to have an idea of
some of the targets FOXP2 is switching
on and off in neural tissue, which in a
perfect world would be those already
implicated in brain patterning.
Together with collaborators at the
Institute of Child Health, he is also
looking to see when and where the
FOXP2 gene itself is switched on in early
brain development during mouse and
human embryogenesis. He will be comparing these results with those from in
vivo imaging of the brain to see which
areas are important for the acquisition of
spoken language. One of the key questions is whether we can line up the
molecular data with regions implicated

in adults from imaging, says Dr Fisher.

The picture building up is that FOXP2 is
only active in specific regions of the
brain and is therefore likely to be having
its effect by directing the fate of certain
types of neurons during development.

Origins
Perhaps one of the most fascinating lines
of research opened up by the discovery of
FOXP2 is the evolutionary origins of
speech and language. FOXP2 stands
out, says Dr Fisher. Its very unusual
from an evolutionary point of view.
With Svante Pbos group in Leipzig,
he has found that just two amino acids
distinguish the FOXP2 protein in humans
from the protein in our closest relative, the
chimpanzee, and that these amino acids
have persisted unchanged in modern
humans. FOXP2 appears to have been
selected during recent human evolution
sometime within the last 200 000 years.
The estimate of when the humanspecific form of FOXP2 became established in the population is intriguing as
it is around the time of a population
growth of modern humans believed to
be driven by the appearance of a more
proficient spoken language, probably
some 50 000 years ago. Could it be that
the tiny changes in the FOXP2 gene
helped to set our distant ancestors on the
evolutionary trajectory that has led to
modern human culture?
JI
Left: Dr Simon
Fisher examining
the structure
of the FOXP2
protein.

2003 Q1 Wellcome News

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